Nalmefene is a known opioid system modulator, with a distinct μ, δ, and κ receptor profile, which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists derived from the opioid system. The clinical usefulness of nalmefene comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists.
Nalmefene has been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect at doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al., Alcohol. Clin. Exp. Res., (2007), Vol. 31 (7): 1179-1187; Trial watch: Nalmefene reduces alcohol use in phase III trial, Nature reviews Drug discovery (2011) Vol. 10 (8): 566). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.
Nalmefene is an opiate derivative structurally related to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half-life, higher oral bioavailability and the absence of dose-dependent liver toxicity.
Nalmefene can be produced from naltrexone by the Wittig reaction. Methods for preparation of nalmefene from naltrexone by the Wittig reaction has been described by Hahn et al., (J. Med. Chem. (1975) Vol. 18: 259-262, Mallinckrodt (U.S. Pat. No. 4,751,307), Meltzner et al., (U.S. Pat. No. 4,535,157) and by H. Lundbeck (WO 2010/136039). By using the abovementioned methods, the free base of nalmefene is obtained, which subsequently can be converted into the hydrochloride salt by use of conventional methods.
WO 2010/063292 discloses nalmefene hydrochloride dihydrate and methods for its manufacturing. The dihydrate form is the preferred crystalline form of nalmefene hydrochloride because its non-hygroscopic properties improve the API stability under storage and formulation conditions. Nalmefene hydrochloride dihydrate can be manufactured by re-slurry or by re-crystallization of nalmefene hydrochloride from an aqueous solution as disclosed in WO 2010/063292. By the re-slurry method disclosed in WO 2010/063292, nalmefene hydrochloride is mixed with an aqueous solution to obtain a suspension, whereupon the mixture is stirred and the solid is isolated. By the re-crystallization method, nalmefene hydrochloride is mixed with an aqueous solution and heated to obtain a substantially homogenous solution whereupon the solution is cooled and subsequently seeded with nalmefene hydrochloride whereupon the formed solid is isolated.
Due to the solubility of nalmefene hydrochloride in water, a considerable amount of the product is lost in the mother liquor from said re-slurry and re-crystallization methods as illustrated by below reaction scheme. Up to 25-35% of the nalmefene hydrochloride may remain in the mother liquor.

Thus, methods to improve recovery from the mother liquor will greatly improve process yields and thus lower overall production costs.
Furthermore, certain impurities are enriched in the mother liquor. Impurities in the mother liquor can be divided into two groups. Morphinan related compounds, mainly naltrexone, and phosphorous by-products generated when nalmefene has been synthesized from naltrexone by the Wittig reaction. Particularly naltrexone, the synthetic precursor of nalmefene is difficult to remove selectively in the recovery process since naltrexone has chemical properties very similar to those of nalmefene.
One process for recovery of un-precipitated nalmefene hydrochloride from the mother liquor of the re-slurry and re-crystallization methods is disclosed in WO 2010/063292. The recovery process of WO 2010/063292 comprises basification of the mother liquor followed by extracting with an organic solvent. The organic solvent is isolated and nalmefene is precipitated from the organic solvent by acidification with hydrogen chloride.
There is a need to find new and improved processes for recovery of nalmefene hydrochloride from aqueous compositions containing nalmefene and certain impurities, such as from mother liquors obtained from methods of preparation of nalmefene hydrochloride dihydrate. In particular there is a need for new and improved processes giving nalmefene hydrochloride in a highly pure form.